The treatment of chronic wounds represents a significant burden on the healthcare system. Currently, between 1-3% of the population in Australia suffer from chronic wounds which translates to a healthcare cost of upwards of $500 million per annum.
Chronic wounds can have a debilitating effect on sufferers and impacts negatively on their quality of life. The treatment of pain related to the wound is often identified as one of the main priorities in chronic wound management. In extreme cases amputation of the affected limb is necessary.
There is currently no single accepted treatment for chronic wounds. Topical treatments using growth factors have been shown to be only partially effective. It has been suggested that this kind of treatment has had limited success due to the high levels of proteases found in the chronic wound fluid resulting in degradation of the growth factors. Matrix metalloproteinases (MMP's) in particular are found in high levels in chronic wound fluid and they have been held responsible for the degradation of the extracellular matrix as well as key factors, including growth factors, critical to wound healing. To address this, some treatments have focused on inhibiting one or more MMP's to reduce the proteolytic environment.
U.S. Pat. No. 5,652,227 discloses the use of bisphosphonates as MMP inhibitors to reduce the excessive degradation of connective tissue matrix protein components in mammals. Inhibition of MMP-1 and MMP-8 using clodronate is stated as particularly desirable. The bisphosphonate is delivered orally, intravenously, or topically i.e. the intention is to make the bisphosphonate available systemically as well as to the wound tissue and wound fluid.
PCT publication WO 2006/126926 teaches that a suture thread with an MMP inhibitor adhered to it may be useful to prevent weakening or softening of the tissue surrounding the sutures after surgery. The inhibitor may be adhered to the suture thread by adsorption, electrostatic interaction or covalent bonding. The aim of this invention is, therefore, to have MMP inhibitors in direct contact with the tissue which is sutured to inhibit tissue degradation and so, loosening of the sutures.
Local contact between the tissue and inhibitor is favoured over systemic delivery. However, it is stated as being desirable that the MMP inhibitor should be gradually released from a fibrinogen matrix associated with the suture thread and so a combination of covalent and electrostatic loading is the preferred means of adherence to the suture thread. A large proportion of the MMP inhibitor is therefore to be released into the tissue in and around the wound.
WO 2002/40058 discloses a bisphosphonate covalently bound to a polymer such as poly(ethylene glycol) which also has a biologically active agent bound via a degradable linker. The bisphosphonate in this invention is employed solely for its hydroxy-apatite targeting ability.
The bisphosphonate is used to target the polymer to bone surfaces and as the degradable linker degrades the biologically active agent is released. This allows the bone surface to be used as a reservoir for a releasable biological agent. The bisphosphonate is present purely as a targeting moiety which is made available systemically via a number of possible delivery routes.
It has been reported that the role of MMP's in chronic wounds may not be as simple as was first thought and the destructive role they play in creating the proteolytic environment of the wound fluid may only represent part of the picture.